Transformative Medical Materials
Authors: Laura De Laporte, Fabian Kiessling
Journal: Advanced Healthcare Materials (2023)

After decades of research in tissue engineering, electronic implants, and drug delivery systems, the ability to create functional in vitro human tissue models and the full restoration of bodily functions are still challenging, making the cure of many diseases impossible. In this context, a wide variety of materials, cells, and technologies have been designed and produced but only a few have been successfully translated into the clinic. Our hypothesis is that most material systems lack the ability to mimic native tissue structure and function, sufficiently integrate into and interact with the organism, adapt their morphology according to an organ's remodeling and growth, induce sufficient vascular supply, and/or actively respond to a changing environment (e.g., inflammation). Therefore, we believe that the development of transformative medical materials that can be programmed to locally respond to internal and external triggers, present and deliver the right signals in a temporally controlled manner, and monitor and stimulate tissue during growth and recovery could overcome many of these limitations. To bring medical materials into clinical practice, early convergence is required across the whole product chain, from basic science and synthesis to biofabrication, automation and good manufacturing production, leading to pre-clinical and clinical testing. Here, regulatory affairs and ethics need to be considered from the beginning on and computational methods may accelerate and improve development and translation. In current practice, medical materials are often designed based on a one directional influence that material properties have on cells. Now, scientists are of the opinion that these materials should do much more than present a comfortable milieu for the cells to thrive, as their spatial organization and temporal functionality are likely to be crucial to form healthy tissue. When transformative medical materials interact effectively with biological interfaces and actively direct cell behavior, biohybrid constructs may be better transformed into fully biofunctional tissues. Ideally, material signals, in combination with bioactive factors and external stimuli, that recapitulate some aspects of native organogenesis, remodeling, and regeneration could promote proper tissue formation. The challenge here is to present harmonious combinations and gradients of biochemical, mechanical, and physical signals in a precisely timed sequence targeting specific cell populations, aligning the appearance of these signals with the distinct developmental programs that are known to guarantee organ-specific differentiation. In this special section of Advanced Healthcare Materials, we present four perspective articles where we describe the state-of-the-art, current challenges, and potential solutions to design, produce, and translate transformative materials in four fields that, in our opinion, can greatly support and push each other forward: in vitro human tissue models, in vivo regenerative systems, biontronics (biologization iontronics), and drug delivery systems. To achieve notable advancement in these fields, we are convinced that different research areas have to merge, such as (bio)chemistry, materials science, (stem) cell biology, biofabrication, and computational modelling. The first paper titled "Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner" by Laura De Laporte and co-workers (article 2301030) centers around the endeavor to develop human in vitro tissue models that accurately replicate real-life processes, thereby unveiling both physiological and pathological mechanisms. By utilizing representative in vitro systems, we can gain a comprehensive understanding of underlying mechanisms, explore human-specific processes, discover novel pharmaceuticals, evaluate therapeutic options, and propel the field of personalized medicine forward. The recent revisions in the regulations of the US Food and Drug Administration (FDA), which eliminate the mandatory requirement of animal testing for drug approval, coupled with the European Medicines Agency's (EMA) endorsement of the 3R Principle (replacement, reduction, refinement), mark a significant paradigm shift. The EMA strongly advocates for the adoption of New Approach Methodologies (NAMs) to establish efficient and dependable alternatives for animal studies. To re-create human tissues and organs in the petri dish and establish reproducible human (disease) models as NAMs, transformative materials have to be compatible with automation, standardization, and high-throughput technologies. The second paper titled "Lifelike Transformative Materials for Biohybrid Implants: Inspired by Nature, Driven by Technology" by Alicia Fernández Colino, Stefan Jockenhoevel, and co-workers (article 2300991), focuses on tissue engineering approaches to replace or regenerate damaged tissues in vivo. It discusses potential reasons why successes in the clinic are limited and how transformative medical scaffolds could overcome some limitations. Two main categories of scaffolds can be distinguished; those that trigger endogenous cells to infiltrate and interact with the material to form new tissue, and those that are employed to pre-grow tissue ex vivo to be implanted in vivo. Many current approaches result in tissues that are not structured as the native tissue, and do not function long-term due to their lack of healthy tissue and instability. We hypothesize that transformative materials that present the required material properties and regenerative signals throughout the regenerative process can achieve more stable and functional tissue to enhance the patient's quality of life. The third paper with the title "Toward the Next Generation of Neural Iontronic Interfaces" by Francesca Santoro and co-workers (article 2301055), discusses the field of biontronics. Biontronics is a term that is introduced to represent the biologization and biointegration of electronic medical devices. Over the past decades, several devices have been developed to readout, integrate, play back, and modulate cellular electric function within excitable tissues, such as nerves, the brain, or cardiomyocytes. These include durable, easy-to-use electrodes and interfaces to facilitate a multi-site, flexible and reliable assessment of peripheral nerve fiber subclass activity in patients. The development of electrodes detecting specific neurotransmitters combined with high-resolution electrical signals will guide diagnosis and therapy selection for several neuronal dysfunctions that severely affect patients and manifest in multiple ways including pain, epilepsy, paraplegia, cardiac arrhythmia and even sensory failure, such as blindness and deafness. Unfortunately, these conditions are notoriously difficult to treat using currently available medical solutions due to slow and undirected neurite outgrowth, lack of or very limited renewal of neurons and cardiomyocytes once injured, and complex disease mechanisms, including impaired electrical function. In the fourth and last paper of this series, titled "Transformative Materials for Interfacial Drug Delivery" by Twan Lammers and co-workers (article 2301062), the current challenges of drug delivery systems are discussed and the future medical needs are addressed, with regard to precision drug targeting and therapy, and novel materials and methods for temporally and spatially controlled drug delivery. The drug delivery systems described range from small-molecule prodrugs, nanomedicines, and microbubbles to milli- or centimeter-sized regenerative medicine implants with micro- or millimeter-sized meshes. Both can be activated on-demand and in situ via external triggers, such as ultrasound, or respond to internal stimuli, such as shear stress, tissue-stiffening, or (reactive) oxygen levels. The authors suggest a new methodology that is conceptually very different from previous efforts in the drug delivery field, aiming to engineer systems that increasingly autonomously interact with and/or respond to cues provided by the pathophysiological microenvironment, as well as by the interfaces that exist between implanted medical materials and host tissue. In summary, transformative medical materials may be a game-changer to create functional human in vitro models, to address the low regenerative capacity of diseased tissue, to improve the poor interaction of implant materials with host tissue, and to enhance the efficacy of drugs by delivering them where they are needed at the right time. We hope you enjoy these four perspective papers. Laura De Laporte is an associate professor at the RWTH University Aachen and a member of the scientific board of the DWI-Leibniz Institute for Interactive Materials. Her research combines engineering, chemistry, and biology to design synthetic biomaterial systems that control and direct the interaction with cells. Her team designs injectable polymeric hydrogel precursors, consisting of nano- and micron-scale building blocks that interlink to form macroporous 3D cell scaffolds, orient after injection to grow anisotropic tissues, and actuate to include movement into the growing tissues. She focuses on spinal cord and cartilage repair and the formation of mini heart tissue models. Fabian Kiessling is leading the Institute for Experimental Molecular Imaging and is one of the directors of the Helmholtz Institute for Biomedical Engineering at the RWTH-University in Aachen. The aims of his research are the development of novel diagnostics, therapeutic and theranostic probes, as well as the advancement of novel imaging technologies and image analysis tools. In this context, a main focus of his research is the investigation and diagnostic assessment of vascular and microenvironmental tissue properties and the exploration of their impact on disease progression, drug delivery, and therapy responses.